Dr White discussing the BCPP findings with Dr. John Kane, who did the first controlled trial of clozapine in North America.

ABSTRACT

Although clozapine is the standard for treatment-resistant psychosis, 40-60% of those treated with clozapine do not have an adequate response as measured by a 20% or greater reduction in the BPRS, PANSS or other assessments. This condition is known as clozapine resistance, ultra-resistance or refractory psychosis. At the publicly funded BC Psychosis Program, at UBC Hospital in Vancouver, Canada, we have developed criteria to identify clozapine resistance (CR) and an algorithmic approach to treatment based on available evidence. This involves assuring adequate clozapine treatment verified by dose and serum level, including addition of fluvoxamine when appropriate; offering ECT to CR patients, and/or antipsychotic augmentation preferably with sulpiride or aripiprazole. All patients admitted since program inception in February 2012 had failed at least 2 antipsychotic trials. A psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist evaluated each patient. All available summaries of previous psychiatric admissions were reviewed, and medical, pharmacological, social and behavioural histories were recorded.

All information is presented at a case conference and a DSM-IV or -5 multiaxial diagnosis reflects agreement among at least 2 psychiatrists and a psychologist. Symptom ratings included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Psychopathology (GAPS), and the Clinical Global Impression-Severity and Improvement scales (CGI). Clozapine resistance is defined by an adequate trial, that is, at least 500 mg daily dose for ≥60 days; and continued symptoms manifested by PANSS with 2 positive scale items rated ≥ 4 (moderate) OR 1 item ≥ 6 (severe).

Of 114 patients with schizoaffective disorder or schizophrenia on clozapine at admission, 89 had received it for≥ 60 days; 23 were on at least 500 mg; and 20 met criteria for clozapine resistance (i.e., 17 men and 3 women). Of these, 17 had schizophrenia and 3 schizoaffective disorder; the mean age was 39.6 years. The mean PANSS scores at admission were Positive=28.3, Negative=26.2, General=50.0, Total=104.4; the mean CGI-S was 6.3. Of 16 patients with complete data, 8 were offered ECT and 3 accepted a course; the number of ECT treatments ranged 19-46. Of 19 patients discharged to date, 17 remained on clozapine with a mean dose of 463.2 mg; to obtain a therapeutic clozapine level, 6 received fluvoxamine, dose range 37.5-200 mg. Seven patients received adjunctive antipsychotics: 3 sulpiride, 2 aripiprazole, 4 first-generation agents. At discharge, the mean PANSS were Positive=20.8, Negative=22.1, General=40.0, Total=82.9; the mean CGI-S was 5.1.

Find full info on the American Psychiatric Association 2017 Annual Meeting here!

When psychiatric patients are treated in an emergency department, they are often hypervigilant, manic, or otherwise in an excited, agitated state. The current standard of care to manage acute agitation in adults is using an antipsychotic medication and a benzodiazepine, often loxapine or haloperidol and lorazepam. For patients who have schizophrenia, antipsychotic medication alone often treats such symptoms in the longer term, yet many patients are discharged with a benzodiazepine prescription continue long-term benzodiazepine use possibly because the community clinician hopes to avoid triggering a relapse in discontinuing the medication. As a psychiatrist who has worked on acute and tertiary inpatient units, I have discharged patients on benzodiazepines with the expectation it would eventually be discontinued, but I have also seen many patients for whom it never was.

What changed my practice

Then, in 2013 while at the 7th Annual Pacific Psychopharmacology Conference, I was introduced to research showing that people with schizophrenia on chronic benzodiazepine therapy have an increased risk for suicide and all-cause mortality. I kept these observations in the back of my mind and was further alarmed in 2016 when another article from the same researchers found high-dose benzodiazepine use, but not lesser doses, was associated with increased suicide and cardiovascular mortality.

What I do now

Based upon these studies, I find the evidence compelling that benzodiazepines are contraindicated for long-term use in people with schizophrenia. When appropriate, I continue to use lorazepam for acute agitation amongst other reasons, I also educate patients about the risk of long-term use, including dependence and cognitive impairment in addition to mortality.To raise awareness of this issue among my colleagues, I mention the rationale and include recommendations for tapering benzodiazepines in consultation reports and discharge summaries.

Patients with psychosis often accumulate medications during hospitalizations and changes in prescribers. The use of multiple medications, often with uncertain benefit, is called polypharmacy. The use of more than one antipsychotic is considered problematic and may increase the risk of adverse effects such as weight gain and diabetes, but other kinds of psychiatric medications often accumulate as well, including antidepressants and benzodiazepines. The latter are used for a variety of reasons, often for acute agitation in an emergency setting, but also for insomnia or chronic anxiety. They may be associated with tolerance, escalating dosage and dependence, although overall are considered safe medications.

Population-based studies from Finland and Denmark have revealed that patients with schizophrenia, however, may be at elevated risk for death when treated with a benzodiazepine. Now the same has been found in a US cohort. Researchers from Ohio State University examined outpatients covered by US Medicaid, age 18 to 58 years old, who had received a diagnosis of schizophrenia during 2007 to 2009. They looked at prescription claims for benzodiazepines, antipsychotics, antidepressants and mood stabilizers from time of diagnosis through 2013. They then examined death certificate files for deaths among the 18,953 identified subjects and calculated hazard ratios for all-cause mortality, death from suicide and accidental poisoning, and death by natural causes.

Of 18,953 patients with schizophrenia, 3,476 received a benzodiazepine, and those subjects were more often Caucasian females who were separated or divorced. The top 3 benzodiazepines prescribed were, in order, lorazepam, clonazepam and alprazolam. In patients taking an antipsychotic, in comparison with those who had no added benzodiazepine, the adjusted hazard ratio after initiating a benzodiazepine was 1.48, i.e. a 48% increased risk of death during the time of cotreatment. For patients who received only a benzodiazepine and no antipsychotic or other medication, the adjusted hazard ratio was 3.08. The calculated mortality rate per 1000 person-years was significantly elevated in every examined combination of medications, e.g. for a mood stabilizer alone, or for an antidepressant plus an antipsychotic, when a benzodiazepine was added. Furthermore, the risks of death from suicide, accidental poisoning and natural causes were all elevated.

The investigators caution that this is an association, and that benzodiazepines cannot yet be implicated as a definite cause of premature mortality in people with schizophrenia. However, this evidence adds to existing epidemiologic findings to make the risk-benefit ratio of benzodiazepine prescription less favorable. The possible mechanisms behind the risk could be multiple, and the researchers mention lower mood and impulsiveness which may occur during benzodiazepine use along with withdrawal-related anxiety as factors that could elevate risk of suicide. As for natural causes, some evidence exists for heightened incidence of infectious diseases concomitant with benzodiazepine use. Prospective studies and larger epidemiologic investigations are required to understand this association, but prescribers should always keep in mind the maxim “do no harm” and attempt to eliminate unnecessary medications.

With modulating dopamine as the primary pharmacotherapeutic option to treat schizophrenia, we are left unable to adequately treat at least 30% of our patients, Dr. Christoph Correll told the audience at the 2016 Pacific Psychopharmacology Conference in Vancouver. The evidence for combining dopamine antagonists, whether first- or second-generation antipsychotics, is not favorable according to a meta-analysis he described which is in review for publication. When only high-quality studies were included, which involved 14 trials with 938 subjects, the evidence for combining antipsychotics melted to nothing. Although it makes sense that using two medications with the essentially the same mechanism of action would not be synergistic, many practitioners nevertheless do just that.

Dr. Correll, who is Professor of Psychiatry at Hofstra Northwell School of Medicine and Medical Director of the Recognition and Prevention Program at the Zucker Hillside Hospital in Queens, New York, said that adding agents with a different mechanism of action may be more promising. Topirimate acts to inhibit activity in the glutamate-NMDA receptor complex and is approved as an anticonvulsant. It also counters the weight gain of psychotropic medications by reducing appetite and enhancing insulin sensitivity. He and six coauthors have recently published a meta-analysis of 16 randomized, controlled trials including a total of 934 patients who received topirimate adjunctive to antipsychotic therapy; outcome data included PANSS or BPRS total scores and body weight, and secondary outcomes included positive and negative symptoms and various metabolic measures including waist circumference and serum glucose.

The benefit for augmentation was significant as measured by total PANSS or BPRS for the entire group, and sensitivity analyses showed it held true with a dose of 150 mg per day or less, in first and multi-episode patients, and either with clozapine or non-clozapine antipsychotics. The effect was independently significant for positive and for negative symptoms. Topirimate was associated with a significant reduction in weight with a mean reduction of 2.75 kg; other metabolic measures were unchanged except for significant reduction in serum triglycerides and fasting insulin. Although discontinuation for adverse effects or inefficacy did not differ with topirimate or placebo, notable adverse effects of topirimate included concentration problems and paresthesias.

These studies were all short-term with a mean duration of 11.8 weeks, a problem with many clinical trials in psychiatry given that schizophrenia is a chronic disorder and patients remain on medication for months to years. Cognitive problems including word-finding difficulty are a known effect of topirimate, and in an illness in which cognitive impairment is inherent, this could be a major liability. Longer-term effects on cognition, metabolic outcomes and psychosis are needed. Will topirimate be the NMDA-modulating treatment that makes a difference or end up like lamotrigine, abandoned after a brief dalliance?

In 2013, Drs. Jaime Hallak, Joao Paulo Maia-de-Oliveira and associates in Ribeirao Preto, Brazil, published results from a randomized controlled trial of intravenous nitroprusside in schizophrenia. Two Canadian researchers from the University of Alberta collaborated on the trial. This study was the first to find that sodium nitroprusside, a treatment for hypertensive crises, has a rapid and prolonged effect on both positive and negative symptoms in patients with acute psychosis. The presumed mechanism is enhancement of nitric oxide in the central nervous system, which may modulate the NMDA receptor-cGMP pathway. In normotensive patients, nitroprusside has minimal effect on blood pressure, and cyanide accumulation is a theoretical concern but occurs only after 72 hours or more of continuous infusion. In treating schizophrenia, the infusion dose is 0.5 mg/kg/minute for four hours.

In the initial trial published in JAMA Psychiatry, Hallak’s team used the Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale (PANSS) as outcome measures. A significant effect on certain components occurred within the first two to three hours of treatment, and improvement endured for four weeks. All the patients were also receiving an antipsychotic other than clozapine.

I met with Jaime, Joao Paulo and their team at the University of Sao Paulo Hospital in Ribeirao Preto and was able to observe a treatment. When I first met the patient, whose infusion had begun 10 minutes before, she appeared anxious and tended to avoid eye contact. When I returned 90 minutes later, she was engaged in an art activity and was eager to show me what she had created. She smiled broadly and even tested her English vocabulary a little. The researchers said that they often see an improvement in the patients’ affect over the course of the infusion, and they are trying to find ways to measure this more objectively. Although data are still limited, the effect in treatment-resistant patients tends to be more delayed.

Further studies of nitrous prusside in Ribeiroa Preto are underway, including for treatment-resistant patients, some on clozapine, and on neurophysiologic effects as detected with fMRI and event-related potential. Because the benefits of the treatment begin to wane after four weeks, they are planning a controlled trial of weekly nitrous prusside infusions for four weeks followed by 60 days of observation.
Reference
Hallak JEC, Maia-de-Oliveira JP, Abroa J, et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial. JAMA Psychiatry. 2013;70:668-676. Abstract
Photo: Left to right: Dr. Jaime Hallak, Dr. Joao Paolo Maia-de-Oliveira,Juliana Almeida (audiologist), their patient and her mother

Many of the patients referred to B.C psychosis Program are on clozapine or have received it in the past, and many have had a limited response. Clozapine-resistance is a big challenge for psychiatrists who manage chronic psychosis, and a recent quantitative review of clozapine augmentation strategies provides little guidance or solace. Stefan Leucht and colleagues examined randomized, masked, placebo-controlled studies

of at least two weeks duration in which another drug was added following at least four weeks of clozapine therapy. Whenever possible, they used intention-to-treat data to calculate effect size.

The studies involved a range of medications including antidepressants, antipsychotics, glutamatergic agents, and antiepileptics. Lamotrigine is particularly of interest because Tiihonen’s group performed a meta-analysis in 2009 based on five studies that showed a significant effect for augmentation of clozapine. This group obtained unpublished data from studies that looked at lamotrigine added to a variety of antipsychotics, and intention-to-treat outcomes from the trial by Zocali, the largest study to date with 30 subjects on active therapy. Based on the 2009 meta-analysis, Goff commented that “the addition of lamotrigine in patients who remain symptomatic despite adequate clozapine treatment represents the most promising treatment option currently available.”

Although Tiihonen et al. found insignificant heterogeneity, Leucht et al. did find heterogeneity and concluded that the Zocali study was an outlier. They therefore excluded it from their final analysis. This is the crucial difference between the two meta-analyses and the reason for the sharply divergent conclusions. Four studies of lamotrigine augmentation are negative and one is positive. A closer look reveals that the Zocali trial was 24 weeks in duration, whereas the other trials were 10 to 14 weeks; could this be a crucial difference? Goff is still correct, and rather than throw lamotrigine overboard, we need a replication trial lasting 24 or 30 weeks. We know that the benefits of clozapine may take many months to be fully evident, so we should not expect that clozapine augmentation to be a quick affair.

As for other findings of the Leucht meta-analysis, sulpiride augmentation showed significant impact on both positive and negative symptoms, and citalopram showed significant impact on negative symptoms, but the findings are based on one trial each. A trial of an experimental glutamatergic agent showed a signal. This leaves us with few clear optins but some direction for further research.